The Neurobiology of Autism

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The Neurobiology of Autism
Article in Brain Pathology · November 2007

DOI: 10.1111/j.1750-3639.2007.00102.x · Source: PubMed
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Symposium: Neurobiology of Autism DOI 10.1111/j.1750-3639.2007.00102.x
The Neurobiology of Autism

Carlos A. Pardo1,2; Charles G. Eberhart2
Departments of 1 Neurology and 2 Pathology, Johns Hopkins University School of Medicine, Baltimore, Md.
Corresponding author:
Carlos A. Pardo, MD, Department of Neurology, 600 N. Wolfe St.—Pathology Bldg 627, Baltimore, MD 21287 (E-mail: cpardo@jhmi.edu) or Charles G. Eberhart,
MD, PhD, Department of Pathology, 720 Rutland Ave., Ross 558, Baltimore, MD 21205
Improving clinical tests are allowing us to more precisely classify autism spectrum being identified, it is generally believed
disorders and diagnose them at earlier ages. This raises the possibility of earlier and that genetic as well as environmental
potentially more effective therapeutic interventions. To fully capitalize on this oppor- factors are involved in the pathogenesis of
tunity, however, will require better understanding of the neurobiological changes
ASD (98, 147, 164). This review focuses
underlying this devastating group of developmental disorders. It is becoming clear that
the normal trajectory of neurodevelopment is altered in autism, with aberrations in
on the current knowledge of molecular
brain growth, neuronal patterning and cortical connectivity. Changes to the structure and cellular factors that may contribute
and function of synapses and dendrites have also been strongly implicated in the to pathogenic mechanisms in ASD, and
pathology of autism by morphological, genetic and animal modeling studies. Finally, examines how they might affect the devel-
environmental factors are likely to interact with the underlying genetic profile, and opment and functioning of the central
foster the clinical heterogeneity seen in autism spectrum disorders. In this review we nervous system (CNS).
attempt to link the molecular pathways altered in autism to the neurodevelopmental
and clinical changes that characterize the disease. We focus on signaling molecules THE NEUROANATOMICAL AND
such as neurotrophin, Reelin, PTEN and hepatocyte growth factor, neurotransmitters NEURODEVELOPMENTAL BASIS OF ASD
such as serotonin and glutamate, and synaptic proteins such as neurexin, SHANK and Different approaches, including clinical
neuroligin. We also discuss evidence implicating oxidative stress, neuroglial activation
assessment, neuroimaging and neuro-
and neuroimmunity in autism.
pathological studies have been used to
Brain Pathol 2007;17:434–447. assess the structural and morphological
brain abnormalities in ASD. One con-
sistent finding in ASD is altered brain
INTRODUCTION rodevelopmental milestones are lost and/ growth, which has been extensively docu-
Autism spectrum disorders (ASD) are or other clinical signs worsen (174). ASD mented by Courchesne et al (54). The
the most devastating conditions in the are clinically heterogeneous and can be clinical onset of autism appears to be pre-
broad range of developmental abnormali- associated in up to 10% of patients with ceded by two phases of brain growth
ties known as “pervasive developmental well-described neurological and genetic abnormalities: a reduced head size at birth,
disorders” (175). ASD comprise a complex disorders, such as tuberous sclerosis, fragile then a sudden and excessive increase
and heterogeneous group of conditions X, Rett’s and Down syndromes, although between 1–2 months and 6–14 months of
that include autism, Rett and Asperger in most patients the causes are still age (54, 57). Furthermore, these reports
syndromes, and pervasive developmental unknown (159, 176) (see review by and other recent neuroimaging studies
disorder-otherwise nonspecified (2). The London). The heterogeneity and clinical have shown that an abnormal pattern of
main clinical features of ASD are stereo- variability of autism has prompted some brain overgrowth also occurs in areas of the
typic behaviors and marked impairment in researchers to use the term autisms instead frontal lobe, cerebellum and limbic struc-
communication, social skills and cognition of autism (81). tures between 2 and 4 years of age, a
(129, 174). Clinical signs of ASD are fre- The stereotypic behaviors and marked pattern that is followed by abnormal slow-
quently present at 3 years of age and recent delay or disruption of communication and ness in brain growth (54, 55, 57, 192).
prospective studies in toddlers indicate that social behavior trajectories that characterize These brain regions are intimately involved
abnormalities in social, communication ASD indicate that crucial neuroanatomic in the development of social, communica-
and play behavior that may represent early structures and neurodevelopmental path- tion and motor abilities that are impaired
indicators of autism can be detected as ways may be affected during intra-uterine in ASD. For example, social orienting defi-
early as 14 months of age (124). Abnor- and/or early postnatal brain development. cits in ASD were linked to abnormalities in
malities in language development, mental Several lines of research indicate that ASD frontal brain mechanisms involved in asso-
retardation and epilepsy are frequent prob- are associated with disarrangement of ciating rewards with goal-directed activity
lems in the clinical profiles of patients with neuronal organization, cortical connectiv- (62, 201). A recent clinical study found
autism, and some patients may exhibit fea- ity and neurotransmitter pathways. While that a head circumference >75th percentile
tures of clinical regression, in which neu- the causes of these abnormalities are still is associated with more impaired adaptive
434 The Neurobiology of Autism—Pardo & Eberhart
© 2007 The Authors

Journal Compilation © 2007 International Society of Neuropathology • Brain Pathology
Genes
Neurobiological Trajectories Neurodevelopmental
Maternal Trajectories
Intrauterine 0–10 weeks Neuronal & Cortical
factors organization
Brain 11–20 weeks
Development Synaptic/dendritic Social cognition & Interaction
21–30 weeks
Environment
Infections modeling
31–40 weeks Language and communication
Cortical Networks
Postnatal First year development
Brain Motor development
Toxins Development Brain growth
Brain Second and
Maturation Third year
Altered Trajectories = Autism Spectrum
Disorders
Figure 1. Genetic and environmental factors that influence intrauterine and early postnatal brain development likely alter neurobiological and neurodevel-
opmental trajectories that determine the clinical core of ASD.
behaviors and with less impairment in IQ fMRI of the brain has also shown abnormal mal pattern of growth with an overall
measures and motor and verbal language patterns of activation and synchronization decrease number of neurons (190, 191).
development (182). Neuroimaging studies across different cortical and subcortical These observations suggest that delays and
have also demonstrated an overall enlarge- regions. This includes reduction in the disarrangements in neuronal maturation
ment of brain volume associated with functional connectivity and decreased cor- are important in the pathogenesis of
increased subcortical white matter in the relation of the time series involved in higher autism (55), although the possibility that
frontal lobe, and abnormal patterns of order tasks that include language, working Purkinje cells or other neurons were ini-
growth in the cerebral cortex, amygdala memory, problem solving and social cogni- tially present and subsequently degener-
and hippoccampal formations (see review tion (reviewed by Minshew (147)). ated must also be considered. In addition
by Herbert (95)). A detailed parcellation Post-mortem neuropathological studies to these cytoarchitectural abnormalities,
study of the cerebral white matter showed also show disturbances in neuronal and the structure and number of cortical mini-
increased volume of the subcortical or cortical organization (reviewed in this issue columns, narrow chains of neurons that
outer radiate white matter in all lobes, but by Casanova). Indeed, cytoarchitectural extend vertically across layers 2–6 (151)
most remarkable in the frontal lobe, sup- organizational abnormalities of the cerebral to form anatomical and functional units,
porting the view that an overgrowth of cortex, cerebellum, and other subcortical appear to be abnormal in ASD. Mini-
intrahemispheric and cortico-cortical con- structures appear to be the most prominent columns in brain from patients with ASD
nections rather than interhemispheric con- neuropathological changes in autism (7, are more numerous, smaller, and less
nections occur in patient with autism and 112). An unusual laminar cytoarchitecture compact in their cellular configuration in
language-associated developmental disor- with packed small neurons has been the frontal and temporal regions, as com-
ders (96, 97). Other studies of cortical and described in the classical neuropathological pared with controls ((34) and review by
cerebral white matter volumes are in- studies by Kemper and Bauman, but no Casanova in this issue).
dicative of inter-regional disconnectivity abnormalities in the external configuration Taken together, clinical, neuroimaging
(95–97), potentially resulting in poor inte- of the cerebral cortex were noted (112). and neuropathological studies support the
gration within and across neurobehavioral Cerebellar and brainstem pathology was hypothesis that autisms are disorders of
developmental domains (56, 117). also prominent, with loss and atrophy of neuronal-cortical organization that cause
Other novel neuroimaging approaches Purkinje cells, predominantly in the poste- alterations of information processing at
such as diffusion tensor imaging (DTI) and rolateral neocerebellar cortex. Kemper and different levels of the nervous system, from
functional magnetic resonance imaging Bauman (11, 112) have delineated at least synaptic and dendritic organization to
(fMRI) have also demonstrated disruption three different types of pathological abnor- pathway connectivity and brain struc-
of white matter tracts and disconnection malities in autism: (i) a curtailment of the ture (81, 147). These neurobiological
between brain regions in patients with normal development of neurons in the alterations likely affect the developmental
autism. DTI of the brain reveals reduced forebrain limbic system, (ii) an apparent trajectory of social behavior and com-
fractional anisotropy values in white matter decrease in the cerebellar Purkinje cell munication during early stages of child-
adjacent to the ventromedial prefrontal cor- population, and (iii) age-related changes in hood (124) and appear to be influenced
tices, anterior cingulated gyrus and superior neuronal size and number in the nucleus of by both genetic and environmental factors
temporal regions, suggesting disruption of the diagonal band of Broca, the cerebellar (Figure 1). Some of the morphological
white matter tracts in brain regions involved nuclei and the inferior olive. Most recently, abnormalities (eg, minicolumnar disorga-
in social functioning (9). Interestingly, studies of the amygdala showed an abnor- nization) suggest the events involved in the
The Neurobiology of Autism—Pardo & Eberhart 435
© 2007 The Authors

MET and the HGF pathway. Both
genetic and protein expression studies have
associated the receptor MET and its ligand
HGF with ASD. A recent case–control
study demonstrated a strong association
of a single nucleotide polymorphism
(G-to-C) in a common 5′ promoter of the
MET gene with ASD. The relative risk of
ASD diagnosis was 2.27 in subjects with
the C/C as compared with the G/G geno-
type (32). This study is especially relevant
because the MET gene is located at 7q31
in one of the regions most commonly asso-
ciated by genetic linkage studies with ASD
(104, 220). MET is a transmembrane
receptor that possesses tyrosine kinase
activity (14, 24) and is activated by bind-
ing to HGF, also termed scatter factor
or hepatopoietin A. HGF and MET, are
present in both developing and adult
mammalian brains, suggesting important
functions across a broad range of neur-
odevelopment (115). HGF acts as a
Figure 2. Multiple genes associated with autism spectrum disorders (ASD) appear to influence neurode-
velopment at different stages of prenatal and postnatal life. These genes have specific periods of influ-
neurotrophic factor for motor, sensory
ence (red solid line) during defined stages of brain development (orange boxes), but their influence may and parasympathetic neurons (203), and
extend to later stages of development including adult life (red broken lines). (Brain development graphic influences neuronal migration (169, 170)
concept based on review by de Graaf-Peters and Hadders-Algra. (63)) and dendritic development (91). The
HGF/MET pathway also plays a role in
regulating dendritic morphology in the
pathogenesis of ASD occur early during formation. Environmental factors (159), developing cerebral cortex and promoting
neurodevelopment, perhaps during first including both maternal/intrauterine and neurite outgrowth (170). Decreased levels
and second trimester of gestation. postnatal events, may well modify the of MET itself and altered levels of mRNA
However, there is still uncertainty about underlying genetic substrate and lead to of proteins associated with the HGF/MET
the precise timing of the neuronal and cor- greater abnormalities in neuronal organiza- pathway have been documented in brain
tical changes in ASD. For example, there is tion and cortical network development. tissues from patients with ASD (33). In
lack of clear gyral or cortical lamination In the sections below, we further discuss addition to these genetic observations and
abnormalities (103), a common feature of the range of neurobiological changes in brain tissue findings, we have documented
neurodevelopmental disorders originating ASD, and associate them when possible increased levels of HGF in cerebrospinal
at early stages such as those that occur with potential genetic etiologies. We have fluid (CSF) of patients with autism (211),
during the first or second trimester. attempted to use a neuroanatomical frame- suggesting a potential compensatory feed-
work in organizing this part of the review back mechanism.
GENETICS AND NEUROBIOLOGY OF ASD (Figure 2), while recognizing that many Interestingly, the multifunctional roles
The major role of genetics in autism is of the molecular pathways implicated of the HGF/MET pathway also involve the
clear, as a concordance rate of 60% to 92% in autism have effects on multiple CNS immune system, as studies have demon-
is seen in monozygotic twins. Recent processes. strated expression of MET in dendritic
studies have further documented the cells (161) and during activation of mono-
genetic complexity of ASD, and highlight Neuronal and cortical organization. cytes (12). HGF-stimulated monocytes
the polygenic nature of the disorder (160, Molecular pathways critical for normal increased the expression of chemoattrac-
187, 194, 205, 220). From these and other neuronal and cortical organization that tant factors including MCP-1, MIP-2b,
analyses, it is clear that molecular pathways have been implicated in patients with ASD MIP-1a and IL-8 (13). HGF also exhib-
with the potential to disrupt neurodevel- include those directed by growth factors ited immunosuppressive effects without
opmental trajectories in utero or after birth such as hepatocyte growth factor (HGF) up-regulation of IL-10 or TGF-b (161),
are involved in the pathogenesis of ASD. and its receptor MET, neurotrophic factors findings that suggest HGF/MET signaling
Such pathways may be associated with such as brain-derived neurotrophic factor is involved in regulation of the inflam-
many different developmental processes, (BDNF), serotonin and other neurotrans- matory responses. Because some of the
from neuronal migration and cortical orga- mitters, and signaling proteins such as non-neurological manifestations of ASD
nization to synaptic and dendritic con- Reelin. include immune and gastrointestinal prob-
© 2007 The Authors

lems, the dysregulation of HGF/MET may Neurotrophins and their receptors are rantly spliced in some autistic patients, and
provide a link between dysfunction of the expressed in the neocortex and hippocam- that Cadps2 knockout mice have autistic-
CNS and other organs. pus (102) and these patterns of neurotro- like phenotypes. CADPS2 regulates the
phin expression are activity-dependent exocytosis of dense-core vesicles, includ-
Reelin. RELN, which encodes the and regulated by sensory inputs, electrical ing BDNF-containing vesicles. In addi-
protein Reelin is another gene playing a activity and stimulation (102) (138). tion, the cellular distribution of BDNF in
critical role in cortical patterning that may BDNF and its receptor, trkB, are densely the brain largely overlaps with that of
be involved in autism. Reelin is a secreted expressed on cortical and hippocampal CADPS2 (183, 184).
extracellular matrix protein that controls neurons, and influence both axonal and
neuronal migration, cortical layering and dendritic growth in a highly neuron- Neurotransmitters. Several lines of re-
other aspects of brain development via specific and age-dependent manner (139). search suggest that abnormalities in sero-
interactions with lipoprotein receptors In rodents, the expression of the trkB toninergic, GABAergic and glutamatergic
(reviewed by Forster (77)). It was initially receptor peaks in the first 2 weeks postna- pathways occur in autism (reviewed by
implicated in ASD based on associations tally, but BDNF action on cortical plastic- Zimmerman (225)). Neurotransmitter
between a polymorphic GCG repeat imme- ity continues into adulthood (119, 139). function in the CNS is linked not only to
diately 5′ of the RELN gene and autism in With maturation, trkB becomes enriched synaptic neuronal interactions, but also to
both case-control and family-based studies at the site of glutamatergic synapses other roles including brain maturation and
in an Italian population (166). The fact that and therefore uniquely able to modulate cortical organization. Neurotransmitters
RELN is located on the distal long arm of experience-dependent plasticity (85). and their receptors may act as paracrine
chromosome 7 at a locus (7q22) associated Interestingly, abnormalities in neurotro- signaling molecules in the immature brain
with autism susceptibility added further phins, especially BDNF, have been im- and help control mechanisms that govern
support to the concept that Reelin function plicated in the etiology of several brain neuronal migration and positioning (134).
might be important, as did the reduced disorders that show altered cortical matu- It is well known that activation of specific
levels of Reelin found in post-mortem ration and plasticity, such as schizophrenia GABA and glutamate receptors (GluRs)
studies of autistic brains (73). Attempts to and depression (158, 197). Genetic studies occurs during cell migration, and is
confirm these intriguing preliminary find- and expression of BDNF in serum of involved in regulating radial and tangential
ings have yielded varied results. Some patients with ASD have pointed out poten- migration (134). Because of these diverse
reports have supported an association tial links to the pathogenesis of autism. functions, neurotransmitters and their
between genetic changes in the RELN locus Nelson et al found elevated levels of BDNF receptors are clearly capable of playing
and autism (196, 199, 224), while others and NT4/5 by assessment of archived neo- central roles in the wide variety of neuro-
have not (22, 66, 118).Transgenic mouse natal blood samples of ASD patients (155). biological alterations associated with ASD.
studies are also suggestive, but not defini- Elevation of BDNF was also reported in The role of serotonin in autism has been
tive, with some social changes and defects in a study of 18 Japanese children with ASD explored using biomarker, neuroimaging
cortical layering observed in mice mutant in as compared with controls (148), and and genetic approaches (193). The most
RELN alleles (186). the authors suggested hyperactivity of this relevant brain imaging studies used
growth factor may be involved in neuro- positron emission tomography to show
Neurotrophins. Neurotrophic growth biological abnormalities in autism. Similar that young children with autism lacked the
factors, or neurotrophins, are good candi- findings were reported in a study of Ameri- developmental peak in brain 5-HT synthe-
dates for involvement in ASD because of can children with ASD, where elevation of sis capacity seen in typically developing
their fundamental roles in guiding CNS BDNF was demonstrated along with the infants (36) (41). Reduced synthesis of
development and cortical organization, presence of auto-antibodies against BDNF 5-HT was observed in dentatothalamocor-
and their abnormal expression patterns in (47, 153, 206). tical pathways, with simultaneous increases
autistic individuals. The core functions of It is still unknown how these observa- in the contralateral dentate cerebellar
neurotrophins during neurodevelopment tions fit into the neurodevelopmental nucleus (41). More recently, SPECT
include regulation of cell proliferation, pathogenesis of ASD, and it is unclear studies demonstrated significant reduc-
migration and survival, and extend to whether the increase in BDNF is a primary tions in 5-HT2A binding in the cerebral
include the modulation of axonal and pathogenic mechanism or a secondary cortex (152). Elevated levels of serotonin in
dendritic outgrowth, synapse formation reaction to cortical abnormalities in ASD. the platelets of patients with autism has
and other neuroplastic processes (5). The However, one report suggesting that also been observed by a number of groups
neurotrophin family consists of at least genetic changes in autistic individuals (29, 48, 123). In contrast, studies that
four proteins, including nerve growth account for altered neurotrophin levels assess changes in 5-HT receptors in plate-
factor, BDNF, neurotrophin-3 and supports the notion that BDNF dysregula- lets or whole blood of individuals with
neurotrophin-4 (92). Their potential role tion could be a primary factor in the devel- autism show decreased 5-HT2 receptor
in pathogenic ASD pathways has been opment of autism. CADPS2 is a gene binding (51, 140).
examined in several studies involving a het- found in the AUTS1 susceptibility locus Genetic studies have also identified
erogeneous groups of neurodevelopmental for autism on 7q31 (42). Sadakata et al abnormalities in serotonin-related genes.
disorders (146, 155, 179). have recently shown that CADPS2 is aber- Tryptophan hydroxylase-2 (TPH2) is the
© 2007 The Authors

rate-limiting enzyme in 5-HT synthesis in effects (137, 219), as barrel formation is disturbances of the glutamatergic system
the CNS, and one group found a particular restored in MAOA and 5-HTT single and may well affect cortical development and
variant of TPH2 to be associated with double knockouts by the blockade of sero- plasticity, as experimental evidence suggests
autism (53). A second study, however, was tonin synthesis, or the additional knockout that GluRs play roles in the activity-
not able to confirm this (181). Polymor- of 5-HT1B receptors, which normally dependent refinement of synaptic connec-
phisms in the promoter region of the sero- inhibit glutamate release (185). tivity (65). GluRs are classified broadly into
tonin transporter gene SLC6A4 have also The interaction of serotonin pathways two groups, ionotropic sites, linked to ion
been reported to be associated with autism with neurotrophins such as BDNF suggests channels and metabotropic sites, linked to
and cortical gray matter volume (39, 52, a potential interplay between these factors second messengers (144). The ionotropic
67, 204, 213, 215). Finally, the gene in ASD pathogenesis. BDNF and serotonin sites include those activated by the
ITGB3 has been proposed as a regulator of show co-regulation in response to environ- exogenous agonists, NMDA, amino-3-
serotonin levels in autism based on genetic mental factors (25, 136). During brain hydroxy-5-methyl-4-isoxazole propionic
association studies (214, 215). Synergistic development, factors such as perinatal stress acid (AMPA) and kainate (KA). NMDA
interaction between the SLC6A4 and or environmental enrichment lead to long- receptors influence both the retraction of
ITGB3 loci has also been suggested (58). term alterations in BDNF expression in incorrectly placed axon arbors and synapses
Another line of research supporting brain and blood plasma (25, 79). In rodent and the elaboration of correctly positioned
serotonin as a neurobiological factor in models, maternal infection can cause long- terminals. NMDA receptors also have well-
ASD comes from pharmacological inter- term increases in BDNF within the cerebral documented roles in cortical development
ventions. Drugs acting on the 5-HT2 cortex and other brain areas that eventually and activity-dependent plasticity (89, 134).
receptor (28, 143) alter the serotonin affect the development of serotoninergic GABAergic pathways also play impor-
system and have caused behavioral im- pathways (83). Another example of this tant roles during brain development, and
provements in autistic patients (94, 101, interaction comes from mice heterozygous the interplay of glutamatergic and
114, 150, 168). Specifically, the selective for BDNF (BDNF+/–) that display prema- GABAergic systems facilitates modeling of
serotonin reuptake inhibitor fluoxetine ture, age-associated loss in forebrain sero- the cerebral cortex by positioning of prin-
causes improvements in social behavior tonergic innervation (130). Similarly, cipal, pyramidal and interneurons (134).
while decreasing aggressive and stereotyped 5-HTT function is impaired in the brains of The establishment of the GABAergic
behaviors in children with autism (6, 27, BDNF+/– mice (61). Localized increases in system and the migration of GABAergic
50, 64, 72, 82). Interestingly, approaches BDNF expression promote 5-HT fiber interneurons are crucial for the develop-
that decrease CNS serotonin such as tryp- sprouting after injury (88, 133). In turn, ment of an inhibitory cortical system that
tophan depletion exacerbated symptoms in 5-HT depletion via inhibition of synthesis regulates the excitatory processes mediated
patients with ASD (49, 142). is accompanied by decreases in BDNF levels by glutamatergic pathways (127). A
A wide range of studies suggest that in the mature hippocampus (223). Such balance between excitation and inhibition
changes in serotonin and other neuro- decreases in BDNF expression may be is crucial for normal development, and its
transmitters can result in aberrant cortical mediated by serotonergic mechanisms in disruption may produce profound conse-
development. 5-HT afferents from the that 5-HT2A receptor antagonists have quences for CNS function and homeostasis
brainstem raphe nuclei innervate cerebral been shown to block stress induced (126). GABAergic interneurons are also
cortex during a critical time in cortical mor- decreases in BDNF expression in the hip- important for processing of information
phogenesis. Similar to the peak in serotonin pocampus and cortex (210). across cortical domains and are part of the
synthesis at 2 years of age in humans, Excitatory neurotransmitter signaling via structure of mini-columns, an essential
rodents show a transient peak in serotonin glutamate receptors (GluRs) also likely module involved in the physiopathology of
levels in the first few days after birth (46, plays a role in cortical development (134), cortical dysfunction in autism (35). The
100). At this time, layer IV of the sensory and has the potential for involvement in the potential involvement of the GABAergic
areas of cortex exhibits dense patches of pathogenesis of ASD. Candidate genes- system in the pathogenesis of ASD has
staining for serotonin and 5-HTTs, particu- screening and association analyses showed been suggested by clinical, neuropathologi-
larly in the “barrel field” in primary that the kainate receptor GluR6 (105, 198, cal and genetic studies. Elevated levels of
somatosensory cortex (18, 60, 78, 178). 202), metabotropic GluR8 (GRM8) (195) GABA in platelets (180) and reduction in
In vivo, it appears that too little or too much and one of four N-methyl-D-aspartate the GABAergic receptor system has been
serotonin is detrimental to cortical develop- (NMDA) receptor 2 subunits, GRIN2A documented by studies of brain tissues
ment. Experimental approaches in rodents (8), appear to be associated with ASD. from patients with autism (16, 17). The
with neonatal systemic 5-HT depletion Interestingly, cDNA micro-array tech- location of three genes for subunits of the
reveal delayed development of several corti- niques along with other mRNA and GABAA receptor, GABRB3, GABRA5 and
cal layers (162), the aberrant appearance of protein studies of brain tissues from patients GABRG3 on the proximal 15q arm (189)
thalamocortical afferent patterning in the with autism identified significant increases prompted genetic studies in ASD that
barrel field (18) and an ultimate decrease in in expression of several genes associated yielded inconsistent results (reviewed by
the size of the barrel field (156, 165). with glutamatergic pathways, including Schmitz (188)). One study that evaluated
Altered dendritic and synaptic development excitatory amino acid transporter 1 and fourteen GABA receptor subunit genes
appears to be at the root of serotonin’s glutamate receptor AMPA 1 (173). Such found an association between GABRA4
© 2007 The Authors

and a potential increase in the risk of trophin, suggesting they could be biologi- 227 individuals with ASD and in 190 con-
autism through interaction with GABRB1 cally significant (217). A Finnish study of trols (69). They identified alterations in a
(131). 100 families with autism yielded a modest small percentage of patients, and showed
association of the disease symptoms with that mutations in a single copy could be
Synaptic and dendritic changes. An the NLGN1, three and four loci, but no associated with language and/or social
early review focused on the neurobiology functional mutations were identified in the communication disorders.
of autism and Rett syndrome helped 30 cases sequenced (221). It has also been
introduce the concept that experience- suggested that the splicing pattern of the Abnormalities in brain growth. Head
dependent synaptic plasticity might be dis- neuroligins is altered in autistic individuals circumference was found to be abnormally
rupted in such developmental disorders (207). In contrast, however, studies of 96 large in a subset of autistic patients by
(227). Dendritic abnormalities can also be autistic patients in Quebec (80), 196 in Kanner in 1943, and approximately 20%
observed in ASD. Indeed, decreased den- Toronto (212) and 124 from an interna- of children with autism have macrocephaly
dritic branching in CA1 and CA4 was tional molecular genetic study of autism (76, 122). As described above, a wide range
reported in one of the earliest analyses of (15) did not identify any genetic alter- of imaging studies have more precisely
pathological changes in autism (177). ations interpreted as being causally linked delineated abnormalities in the growth of
Several leads from genetic studies have also to autism. Furthermore, in at least one the brain as a whole, and of specific regions
implicated synaptic changes in autism. family deletion of NLGN4 was not associ- and structures. Potential molecular causes
These include alterations in the genes ated with autistic symptoms (132). of these size changes are beginning to be
encoding Neuroligins 3 and 4, their Given these somewhat conflicting find- discovered. For example, a polymorphism
binding partners Neurexins 1 and 3, ings, the recent discovery that neurexin, a in the HOXA1 homeobox gene has been
SHANK and contactin-associated-protein- major protein partner of the neuroligin associated with increased head circumfer-
like 2 (CNTNAP2). The neuroligins, a family, is altered in some autistic individu- ence in patients with autism (45). The
family of five postsynaptic cell adhesion als provides key support for the concept cellular basis of brain overgrowth is not
molecules, were the first of these to be asso- that this synaptogenic pathway is involved yet clear, but several theories have been
ciated with autism. In 2003, Jamain et al in ASD development. Feng et al screened advanced. One hypothesis is a reduction in
reported that Neuroligins 3 and 4 were three beta-neurexin genes in 203 patients the pruning and consolidation of synapses
mutated in ASD patients (106). They ini- with autism, as well as in 535 controls (74). during development, leading to an in-
tially examined the locus because it is They found two putative missense muta- creased number of neurites. Increased
located at Xp22.3, a chromosomal region tions predicted to cause structural changes numbers of neurons or glia in the brain,
deleted in several autistic females. When in four autistic cases, but in none of the either through initial overproduction or
they screened 36 pairs of affected siblings controls. Neurexin are presynaptic pro- reduction of cell death, are additional pos-
and 122 trios with autism, they found one teins, and represent the binding partners sibilities. These and other theories are dis-
Swedish family harboring a frameshift for postsynaptic neuroligins. This interac- cussed in more detail in a recent review of
mutation leading to a premature stop tion is thought to trigger postsynaptic dif- brain growth in autism (141). Finally, it is
codon in NLGN4, and another Swedish ferentiation and control the balance of possible that hypertrophy of individual
family with a mutation affecting a highly inhibitory GABAergic and stimulatory cells may cause the brain size increase. An
conserved residue in NLGN3. The glutamatergic inputs (87, 171). intriguing candidate potentially involved
NLGN4 mutation is predicted to represent SHANK3, another synaptic protein in the regulation of brain size in autism via
a genetic null allele, while the changes in which can bind neuroligins, was also this final mechanism is the gene PTEN
NLGN3 result in a protein that does not recently implicated in autism. It was ini- (phosphatase and tensin homolog on chro-
efficiently traffic to the cell surface and tially investigated because of its location mosome 10).
appears to have altered binding abilities on chromosome 22 in a region lost PTEN was initially evaluated in ASD
(40, 44). or rearranged in patients with ASD. patients because it is mutated in Cowden
Subsequent attempts to confirm the role This microdeletion syndrome involving syndrome, a rare autosomal dominant con-
of neuroligin mutations in patients with 22q13.3 is characterized by multiple devel- dition characterized by numerous hamar-
ASD have yielded mixed results. Laumon- opmental delays, dysmorphic features and tomas and an increased risk of cancer
nier et al reported a frameshift mutation in autistic behavior (135). SHANK3, also (167). Inherited PTEN mutations are
the NLGN4 gene in a large French family known as ProSAP2, is one of three genes also found in patients with Bannayan–
with mental retardation, some of whom located in the minimal involved region. It Riley–Ruvalcavba (BRRS) and Proteus
also had autism (125). A mixed cohort of encodes a type of protein found in excita- syndromes. Macrocephaly is a feature of
148 autistic patients from the USA and tory synapses that serves as a scaffold and Cowden syndrome patients, and some of
Portugal contained about 3% with mis- can bind to neuroligins (145). Shank pro- these individuals were reported to be autis-
sense mutations in conserved regions of teins have been proposed as master orga- tic (84, 167). Macrocephaly and autistic
NLGN4, but no changes in NLGN3 nizers of postsynaptic density because of behavior has also been reported in a patient
(218). A functional analysis found that the their ability to nucleate multimeric protein with BRRS (228). Given these common-
R704C mutation described by Yan et al complexes in dendritic spines. Durand et al alities between inherited PTEN syndromes
weakened the binding of neuroligin to syn- recently sequenced all SHANK3 exons in and autism, Butler et al sequenced the
© 2007 The Authors

PTEN gene in 18 autistic patients with dritic hypertrophy and a dramatic increase rophages and endothelial cells, play im-
macrocephaly, and found three with het- in the number of presynaptic vesicle. These portant roles in neuronal function and
erozygous germline mutations (30). A changes are consistent with a previous homeostasis (1, 10, 68, 157, 216). Both
more recent screen of 88 patients with report implicating the AKT/mTOR microglia and astroglia are fundamentally
ASD and macrocephaly identified one pathway, which functions downstream of involved in cortical organization, neuroax-
with a misssense mutation in PTEN, but PTEN, in dendritic arborization (109). onal guidance and synaptic plasticity (75,
no partial or whole gene deletions (31). Tuberous sclerosis (TS) is another 209). Neuroglial cells contribute in a
Several additional cases of autistic indi- genetically defined neurodevelopmental number of ways to the regulation of
viduals with PTEN mutations have also disorder caused by alterations in genetic immune responses in the CNS. Astrocytes,
been reported recently, leading to the rec- signaling pathways that converge with for example, play an important role in the
ommendation that such testing be rou- those controlled by PTEN. TS patients are detoxification of excess excitatory amino
tinely performed (19, 99). It is not yet clear frequently also diagnosed with autism, acids (154), maintenance of the integrity of
if PTEN mutations in autistic individuals with estimated rates of ASD ranging from the blood–brain barrier (172), production
are always associated with increased head 17% to 68% (200). Some investigators of neurotrophic factors (10) and the
size, or if normocephalic autistic patients have found that the numbers or location of metabolism of glutamate (154). In normal
might also have disruptions in PTEN func- cortical tubers in TS is correlated with homeostatic conditions, astrocytes facili-
tion. It will also be interesting to determine autistic behaviors, suggesting these discrete tate neuronal survival by producing growth
if other members of the signaling cascades structural lesions might cause the associa- factors and mediating uptake/removal of
regulated by PTEN are altered in autism. tion (20, 71). Others, however, did not excitotoxic neurotransmitters, such as
PTEN is a phosphatase that regulates find that the number or site of cortical glutamate, from the synaptic microenvi-
signaling through the phosphoinositol 3- tubers correlated with autistic behaviors (3, ronment (154). However, during astroglial
kinase (PI3K) pathway. It has multiple 21). In order to examine this pathway, we activation secondary to injury or in
downstream effects, and regulates cellular performed a preliminary immunohis- response to neuronal dysfunction, astro-
proliferation, differentiation and migra- tochemical investigation of S6 ribosomal cytes can produce several factors that may
tion. In neoplasms, PTEN acts as a tumor protein phosphorylation in post-mortem modulate inflammatory responses. For
suppressor, with loss of function mutations brains from five autistic children and an example, they secrete pro-inflammatory
and deletions causing increased prolifera- equal number of matched controls, but did cytokines, chemokines and metalloprotein-
tion and decreased cell death. In postmi- not identify any major changes (70). ases that can magnify immune reactions
totic neurons, however, loss of PTEN within the CNS (10). Microglial and astro-
function leads to the hypertrophic growth NEUROIMMUNITY, ENVIRONMENT AND glial activation is an important factor in the
without proliferation, resulting in forma- NON-GENETIC FACTORS IN ASD neuroglial responses to injury or dysfunc-
tion of aberrant ganglion cells and a phe- It is clear that genetics alone do not tion. Microglia are involved in synaptic
notype highly similar to that seen in determine the entire ASD phenotype, and stripping, cortical plasticity and immune
Lhermitte–Duclos disease, which is associ- that other non-genetic factors must play surveillance (1, 86). Changes in astroglia
ated with Cowden syndrome (120). roles as modifiers of processes determined and microglia can therefore produce
PTEN has subsequently been deleted by genetic susceptibility. Environment and marked neuronal dysfunction that is likely
from postmitotic neurons of the cerebral epigenetic factors both have the ability to to be associated with mechanisms of neu-
cortex and dentate gyrus in transgenic influence pathogenic mechanisms of corti- ronal dysfunction observed in autism.
mice, leading to some very interesting cal and neuronal function. Among envi- These neuroglial changes are mediated by
behavioral and neuropathological changes ronmental factors, maternal influences and the production of oxidative species, cytok-
(121). These animals showed progressive exposure to neurotoxins and potential ines, chemokines and other neuroactive
macrocephaly, but also were impoverished environmental pollutants have been the substances (10).
in their social interactions. For example, focus of attention in recent investigations. There has been growing interest in the
while wild-type animals will preferentially These may interact with the neuroimmune role of immunity and immunological
interact with a mouse they have not system and disrupt neurodevelopmental dysfunction in the pathogenesis of ASD
previously encountered, PTEN deficient pathways resulting in alterations of neu- (reviewed by Pardo (163) and Ashwood
animals did not. Indeed, the transgenic robehavioral trajectories such as those that (4)). Several reports link the presence of
animals were as likely to interact with an occur in ASD (124, 129). A recent study, immunological dysfunction with autism,
inanimate object as a social target animal. for example, found that patients with and some studies suggest that up to 60%
These behavioral changes may be caused by autism and larger head sizes show a signifi- of patients with ASD have various types
multifaceted neuropathological changes, cant association with a history of allergic/ of systemic immune dysfunction, either
as in addition to increased neuronal size immune disorders both in the patient and as part of cellular or humoral immune
the authors found alterations in axons, in first-degree relatives (182). responses (116, 128, 208). A few earlier
dendrites and synapses in the transgenic case reports found pathological evidence of
animals. Specifically, in mutant animals Neuroglia and neuroimmunity in ASD. immunological reactions within the CNS,
they documented enlargement of mossy Neuroglial cells such as astrocytes and such as lymphocyte infiltration and micro-
fiber tracts, ectopic granule axons, den- microglia, along with perivascular mac- glial nodules (7, 90). Several reports using
© 2007 The Authors

different methodologies and small patient high oxygen demands and limited anti- using immunoblot techniques. In another
populations have shown increases in oxidant capacity, the brain is thought study by Van de Water et al (26), of 61
pro-inflammatory cytokines in peripheral to be relatively vulnerable to oxidative mothers of patients with autism, seven of
blood samples in ASD (see review by stress (111). Several studies have shown the plasma samples (11.5%) contained
Ashwood (4)). Most recently, Molloy et al decreased levels of antioxidants such as maternal antibody cross-reactive with
found an increased pattern of production superoxide dismutase, transferrin and human fetal brain proteins 73 kDa and
of Th2-associated cytokines in leukocytes ceruloplasmin in the blood or serum of 37 kDa in size. This was not observed in
from autistic subjects (149). patients with ASD (38, 108, 222). Signifi- the control group of mothers with typical
Neuropathological studies of post- cant elevations in biomarker profiles indi- developing or non-autistic developmen-
mortem brain tissues from autistic patients cating increased oxidative stress, such as tally delayed children. The presence of such
demonstrate an active and ongoing neu- increased lipid peroxidation, have also been antibodies in the plasma of some mothers
roinflammatory process in the cerebral documented in autism (38, 107, 229). suggests the transfer of maternal antibodies
cortex and white matter characterized by Interestingly, in one report the alterations during early development could interact
astroglial and neuroglial activation. These in antioxidant proteins were linked specifi- with fetal CNS proteins, affecting neu-
findings support a role for neuroimmune cally to regressive autism, suggesting a rodevelopmental pathways and increasing
responses in the pathogenesis of ASD postnatal environmental effect (38). Poly- the risk of ASD.
(211). As both astroglia and microglia morphisms in metabolic pathway genes
are involved in pathogenic inflammatory may contribute to the increased oxidative SUMMARY
mechanisms common to many different stress in autism (108). Advanced glycation In this review, we have attempted to
disorders of the CNS, it is possible that end products have also been reported to be briefly summarize some of what is cur-
different factors (eg, genetic susceptibility, elevated in both the brain tissue and serum rently known about the neurobiological
maternal factors, prenatal environmental of autistic patients, a change which can also causes of autism. Autism and related devel-
exposures) may trigger the development of lead to increased oxidative damage (23, opmental disorders are clinically heteroge-
these neuroglial reactions. Furthermore, 110). neous, and are likely caused by a range of
protein array techniques used to establish factors. This heterogeneity has made it dif-
the profiles of immune mediators demon- Maternal factors. A final interesting area ficult to tease out the individual causal ele-
strated that cytokines/chemokines such of research has focused on the potential ments of this devastating disease. Slowly,
as MCP-1, IL-6 and TGFb1, which are role of maternal factors in the pathogenesis however, genetic and environmental alter-
mainly derived from activated neuroglia, of autism. A study by Comi and Zimmer- ations are being defined, including the
are the most prevalent cytokines in brain man (43) showed that the mean number molecular and genetic changes affecting
tissues (211). Similar findings were seen in of autoimmune disorders was greater in brain growth and development described
CSF from autistic patients. Preliminary families with autism, and that 46% of above. This improving understanding may
studies also show that serum concentra- ASD patient’s families had two or more ultimately lead to new strategies for the
tions of subsets of cytokines and chemok- members with autoimmune disorders. As prevention or cure of ASD. An encourag-
ines, such as MCP-1 and IL-6, parallel the the number of family members with ing recent report provides an example of
CSF levels, suggesting that serum levels autoimmune disorders increased from one such therapeutic progress, as Hayashi et al
may be useful as surrogate markers of neu- to three, the risk of autism was greater, with have shown that the symptoms of fragile X
roinflammatory activity in autistic sub- an odds ratio that increased from 1.9 to syndrome in mice can be reversed by inhi-
jects. These findings strongly suggest that 5.5. The most common autoimmune dis- bition of a specific kinase (93). Similar
neuroimmune reactions are part of the orders observed were type 1 diabetes, adult studies targeting a broad range of molecu-
neuropathological processes in ASD, and rheumatoid arthritis, hypothyroidism and lar factors involved in autism will hopefully
that immune responses are among the systemic lupus erythematosus. However, a eventually allow us to treat the growing
factors that may contribute to CNS dys- large population-based case–control study number of patients afflicted with ASD.
function. However, the significance of the found no significant differences in the pro-
neuroinflammatory response to the specific portion of case and control mothers with a
neuropathologies and behavioral disrup- diagnosis of autoimmune disease in the ACKNOWLEDGMENTS
tions in ASD, and its position in the etiol- 4-year period surrounding pregnancy (59). Dr Pardo is supported by the Peter
ogy of ASD, requires further exploration. Tissue-based studies have also suggested a Emch Fund for Autism Research, The Bart
role for maternal autoimmune factors in A McLean Fund for Neuroimmunology
Oxidative stress. Oxidative stress is the pathogenesis of autism. The presence Research, Cure Autism Now and NIH-
another possible cause of Purkinje cell of maternal auto-antibodies that cross- NIDA (K08-DA16160). Dr Eberhart
loss and other neuroanatomical changes react with brain epitopes was demonstrated receives support from 1R01NS055089-
described in autistic brains (reviewed in by two studies (26, 226). In one study by 01A2.
(37, 113)). Oxidative stress occurs when Zimmerman et al, serum from 11 mothers
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